Molecular Pathway That Enables Movement of Metastatic Cancer Cells Identified

Cancer researchers have identified a molecular pathway that seems to be responsible for the ability of metastatic tumor cells to change shape and travel.

Investigators at the University of Michigan (Ann Arbor, USA) worked with breast cancer cells growing in culture. Previous studies had shown that aggressively metastatic breast cancer cells usually overexpressed the RhoC (aplysia ras-related homolog 9) gene. In this study, they searched for the molecular trigger for RhoC expression.

They reported in the August 23, 2011, online edition of the journal Cancer Research that the protein p38gamma was directly linked to RhoC activation. P38gamma is one member of the p38 MAPK (p38 mitogen-activated protein kinase) class of mitogen-activated protein kinases. These enzymes are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation and apoptosis.

Results from experiments with breast cancer cell cultures revealed that inactivation of p38gamma caused cells to flatten out and shift from fast motion to ineffective movement. Clinical relevance indicated that elevated expression of p38gamma was associated with lower overall survival of breast cancer patients. The critical role of p38gamma was further emphasized by data generated from a mathematical model that described how various molecules contributed to cell movement.

“Normal motion is commonly seen in aggressive cancers, which is why it is very important to understand what the key switches are for this motion,” said senior author Dr. Sofia Merajver, professor of internal medicine at the University of Michigan. “Cell movement is very difficult to observe, which is why mathematical modeling in oncology is valuable. This gives us a more complete understanding of how aggressive breast cancer cells move and the influence of p38gamma in particular on modifying this motion.”

“We do have targeted therapies in the clinic, but the total burden of disease that they ameliorate is still relatively minimal. The reasons may not necessarily be that they are not good drugs, but simply that we do not understand how they work, because we do not understand the biology in sufficient detail. That’s why studies like this are so important in advancing drug development,” said Dr. Merajver.

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